Download Hormone Therapy for Treatment of Menopausal

0806DBT203501hanlay 6/5/08 4:13 PM Page 207
Menopause
Hormone Therapy for Treatment of Menopausal
Symptoms: New Formulations and Methods of Delivery
Cheryl S. Hankin, PhD, Kori Hack, PharmD, BCPS, Jeffrey Dunn, PharmD, MBA, Beckie Fenrick, PharmD, MBA
The use of hormone therapy (HT), widely viewed as the gold standard for treatment of moderate to severe vasomotor symptoms in postmenopausal women,
dramatically changed after publication of the Women’s Health Initiative (WHI)
studies. However, the WHI studies involved predominantly older postmenopausal
women who were not experiencing moderate to severe vasomotor symptoms, and
used different HT compounds, regimens, doses, and modes of delivery than are
now available. Current formulations include bioidentical hormones, lower
hormone doses, and a choice of oral and transdermal delivery systems. This review
summarizes major criticisms of the WHI studies and examines the safety of newer
HT options and the attributes of formulations new to the market. (Drug Benefit
Trends. 2008;20:207-220)
Key words: Hormone therapy • Women’s Health Initiative
• Transdermal drug delivery • Menopause
I
n 2002, the release of findings
from the Women’s Health Initiative (WHI) randomized controlled trials spurred a reappraisal
of the risks and benefits associated
with hormone therapy (HT), then
the standard treatment for menopausal vasomotor symptoms. Although the results of the WHI have
influenced recommendations for the
use of HT in the United States, there
has been considerable debate about
the relevance of WHI findings for
women in early menopause who
experience moderate to severe vasomotor symptoms, the same group
for whom HT is most likely to
be prescribed in clinical practice.1-4
Since the WHI trials, new drug entries have been introduced that offer
lower doses, lower system concentrations, and a choice of formulations. This review is intended to pro-
vide up-to-date and balanced information about the risks and benefits
associated with HT use, giving particular emphasis to the HTs that have
entered the market since the release
of the WHI findings.
WHI Study Findings
The WHI studies were 2 NIH-sponsored, large-scale, randomized, placebo-controlled trials that enrolled
27,347 women aged 50 to 79 years
from 1993 through 1998 to determine
the efficacy of HT in the primary
prevention of coronary heart disease
(CHD) and, secondarily, to assess the
spectrum of long-term risks and benefits associated with HT use. In the
first study, 16,608 postmenopausal
women with an intact uterus were
randomized to receive either conjugated equine estrogen plus medroxyprogesterone acetate (CEE/
Dr Hankin is president and chief scientific officer at BioMedEcon, Moss Beach, Calif; Dr
Hack was director of formulary development, Prime Therapeutics, Eagan, Minn, at the
time this article was written; Dr Dunn is formulary and contract manager, SelectHealth,
Inc, Salt Lake City; and Dr Fenrick is formulary director, Blue Cross Blue Shield of
Florida, Jacksonville.
MPA; Prempro) or placebo.5 In the
second study, 10,739 post-hysterectomy women were randomized
to receive either conjugated equine
estrogen (CEE; Premarin) alone or
placebo.6 (Prempro and Premarin are
products of Wyeth Pharmaceuticals,
Philadelphia.) The planned duration
for both trials was 8.5 years.
The CEE/MPA trial was
stopped early in 2002 after a mean
5.6 years of follow-up when it became apparent that HT increased the
risk of breast cancer and that the
potential benefits of HT use did not
outweigh the risks.7 The relative
risks and benefits were assessed
by the Global Index, a composite
measure of the number of cases of
heart attack, stroke, breast cancer,
endometrial cancer, colorectal cancer, pulmonary embolism, hip fracture, and deaths from other causes.7
Although the absolute numbers of
cases were small, women who received CEE/MPA had a 29% increased risk of CHD, a 41% increased
risk of stroke, a 2-fold greater risk
of venous thromboembolism (VTE),
and a 26% increased risk of breast
cancer.5
In addition, the Women’s Health
Initiative Memory Study (WHIMS),
an ancillary study to the WHI involving a subset of women aged 65
and older, revealed a significant increased risk of dementia in women
receiving CEE/MPA (hazard ratio
[HR], 2.05; 95% confidence interval
[CI], 1.21 to 3.48; P = .01).8 The benefits of CEE/MPA included a 37% decreased risk of colorectal cancer and
a 34% reduced risk of hip fracture.5
Three years after stopping
June 2008 DRUG BENEFIT TRENDS 207
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therapy, women in the WHI studies
who had been treated with CEE/
MPA showed a significantly increased risk of malignancies (HR, 1.24;
95% CI, 1.04 to 1.48), including a
greater but nonsignificant increased
risk of invasive breast cancer (HR,
1.27; 95% CI, 0.91 to 1.78) but no increased risk in cardiovascular events
(HR, 1.04; 95% CI, 0.89 to 1.21).9
In 2004, the study of women
being treated with CEE alone was
also terminated early after a mean
follow-up of 6.8 years when analyses
indicated that use of CEE significantly increased the risk of stroke
(38% increase; P = .007) and did not
reduce the risk of CHD (9% reduction; nonsignificant) or overall mortality (4% increase; nonsignificant).6,10 There was a nonsignificant
trend toward an increased risk of dementia in the CEE group (HR, 1.49;
95% CI, 0.83 to 2.66; P = .18).11 On the
positive side, use of CEE significantly reduced the risk of hip fracture
(39% decrease; P = .01) and showed a
trend toward a reduced risk of breast
cancer (23% decrease; P = .06).6
Recommendations Based on
WHI Study Findings
The WHI studies have significantly influenced recommendations regarding the use of HT and have
changed HT prescribing patterns in
the United States. Following the announcement of the WHI findings,
various organizations, including the
American College of Obstetricians
and Gynecologists (ACOG) and the
North American Menopause Society
(NAMS), recommended that women
should receive HT only for the management of vasomotor symptoms. In
addition, the US Preventive Services
Task Force,12 ACOG,13 NAMS,14,15
and the American Heart Association16 recommended against the use
of HT for primary and secondary
prevention of cardiovascular disease. The FDA recommended that
208 DRUG BENEFIT TRENDS June 2008
women being treated with HT
should take the “lowest effective
doses for the shortest duration consistent with treatment goals and
risks for the individual woman”14-17
and revised its recommendations for
labeling of HT products to include a
boxed warning describing the increased risks of myocardial infarction, stroke, VTE, and breast cancer
associated with HT.18
Publication of the WHI studies
prompted physicians to discontinue
use of HT in many patients; in addition, many patients chose to stop
therapy on their own. The number of
prescriptions dispensed annually for
HT fell from 91.0 million in 2001 to
56.9 million in 2003.17 The greatest
decline was for oral CEE and CEE/
MPA preparations, which accounted
for 80% of the decrease in prescriptions, with smaller declines seen
for transdermal formulations (14%
reduction).17
Criticisms of the WHI Studies
A number of authors have been critical of aspects of the WHI studies
and have questioned whether these
findings are applicable to the women
who are most likely to receive HT in
clinical practice (ie, women with vasomotor symptoms during the transition through menopause).1-4 Conclusions based on WHI study findings have been called into question
for 6 main reasons:
• Participants in the WHI studies
were predominantly older women
in late-stage post menopause, and
findings may not generalize to
younger, early perimenopausal
and early postmenopausal women.
• The WHI study was not designed
or powered to test the benefits
of HT on vasomotor or other
menopause-related symptoms,
and therefore these benefits are
underestimated.
• Although the risk-benefit profile
of the CEE/MPA study was sub-
stantially different from that of
the CEE study, findings are often
commingled.
• WHI study results were predicated
on a specific estrogen-based therapy, and findings may not extend
to other estrogen-based therapies.
• WHI study findings were based on
doses of estrogens that may have
been higher than the lowest effective dose.
• Results were based on a specific
mode of drug delivery and may
not apply to other delivery modes.
• Participants in the WHI studies
were predominantly older women
in late-stage post menopause, and
findings may not generalize to
younger, early perimenopausal and
early postmenopausal women. A
notable criticism of the WHI studies
is that findings based on a sample
of primarily older, late postmenopausal women have been inappropriately generalized to younger,
early perimenopausal and early
postmenopausal women.1-3,19,20 The
average age of women in the WHI
studies was 63 years (approximately
11 years older than the average age
at which menopause occurs),2 with
70% of participants 60 years or
older.5,6 Approximately 83% of participants were more than 5 years post
menopause and 43% were more than
15 years post menopause2; women
within 1 year of menopause were
excluded from participation.4
Because of the older age of most
WHI participants, these women were
at greater risk for preexisting subclinical atherosclerosis, and therefore
would not have benefited from the
potential cardioprotection of HT.4
Supporting this notion is a recently published secondary analysis of
WHI study data showing that the
effect of HT on CHD risk is associated with the woman’s age at HT initiation.21 As seen in the Figure, the
risks of CHD, stroke, and death from
0806DBT203501hanlay 6/5/08 4:13 PM Page 209
Figure. Risk of
coronary heart
disease, stroke, and
death from any
cause in the
Women’s Health
Initiative study
varied by participants’ ages at
hormone therapy
(HT) initiation.
Risk of CHD, Stroke, or Death From Any Cause by
Age at Initiation of HT21
60
Likelihood of outcomes, %
50
Coronary heart disease (CHD)
Stroke
Death from any cause
40
50a
26a
30
21
20
14
13
10
5
0
–2
–10
–7
–20
–30
–40
–30
50 - 59
60 - 69
70 - 79
Age range, y
a
P = .03 for ages 50 to 59 years. Significance threshold set at P = .01 for this study; therefore results not statistically significant.
any cause varied by WHI participants’ ages at HT initiation.
• The WHI study was not designed
or powered to test the benefits of
HT on vasomotor or other menopause-related symptoms, and therefore these benefits are underestimated. In the general population, up
to 75% of women experience hot
flashes during the transition from
perimenopause to post menopause,
lasting 6 months to 2 years.14 Although these symptoms are mild in
severity for many women, 40% to
60% experience moderate to severe
symptoms, and 10% to 20% find
these symptoms intolerable.22 HT is
the gold standard for treating moderate to severe vasomotor symptoms
in postmenopausal women.14
The WHI studies were intended
to evaluate the disease-preventive
effects of HT rather than to evaluate
the potential benefits of HT in the
treatment of menopausal symp-
toms.20 In fact, women with menopausal symptoms were discouraged
from participating in WHI.23 As
such, most WHI participants (88%)
reported no vasomotor symptoms
at study entry2; this is not surprising
given that hot flashes rarely persist beyond the first 5 years of
menopause,24 and, as previously
noted, the majority (83%) of WHI
participants were more than 5 years
postmenopausal.2
WHI investigators found that
12% of WHI participants who reported moderate to severe vasomotor symptoms at baseline noted a significant improvement in hot flashes
(76.7% vs 51.7%, respectively; P <
.001) and night sweats (71% vs
52.8%, respectively; P < .001) in the
first year of treatment compared
with women in the placebo group,
but did not experience a significant
improvement in overall quality of
life.25 Critics have challenged these
findings by noting that WHI partici-
pants were unlikely to experience
significantly debilitating symptoms
by virtue of their willingness to be
randomized to a placebo group for
the intended duration of this longterm trial.20 Because the WHI failed
to include women who were experiencing true moderate to severe vasomotor symptoms, the benefits of HT
may be underestimated.
• Although the risk-benefit profile
of the CEE/MPA study was substantially different from that of the
CEE study, findings are often commingled. Table 1 compares primary
and secondary outcomes, including
risk of dementia as assessed by investigators of the WHIMS,8,11 associated with the CEE/MPA5 and CEE
alone6 treatments. Whereas treatment with CEE/MPA was associated
with a significantly increased risk
of CHD, stroke, breast cancer, VTE,
and dementia, only risk of stroke
was significantly increased for CEE
June 2008 DRUG BENEFIT TRENDS 209
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study participants. Synthetic progestin is recommended for use in
postmenopausal women with an intact uterus to reduce the risk of endometrial cancer presented by unopposed HT15 but is not recommended
for women without a uterus15 because of adverse effects.3
• WHI study results were predicated on a specific estrogen-based
therapy, and findings may not extend to other estrogen-based therapies. In the WHI studies, HT consisted of oral 0.625 mg/d CEE or
oral 0.625 mg/d CEE and 2.5 mg/d
MPA; these CEE-based therapies
were the most commonly used HT
regimens in the United States at
the time the WHI was conducted.3
CEE, derived from the urine of
pregnant mares,26 contains a complex combination of hormone metabolites, some of which have inadequately delineated, unknown, or
antiestrogenic effects.27,28 Although
only 2 components of CEE (estrone
[E1] and estradiol [17-estradiol])
are identical to human estrogens,
they represent about half of the CEE
components.28
In contrast to conventional HT
(CEE), estradiol, a plant-based estrogen, has the same biological structure and physiological effects as
hormones found endogenously in
women.29 As such, estradiol-based
therapies, which are available as oral
and transdermal products, are “bioidentical.” (Note that these pharmaceutical-grade products are distinguished from compounded bioidentical hormone products, which are
custom mixed in pharmacies; are
often untested for purity, potency, efficacy, and safety; and are of variable
quality.30)
• WHI study findings were based
on doses of estrogens that may have
been higher than the lowest effective dose. To meet the recommended
goal of using the lowest effective
doses of HT, doses of less than half
those employed in the WHI studies
are now recommended to reduce
the risk of adverse events.14,15 Data
suggest that low-dose (0.3 mg CEE
Table 1. Risk of Adverse Outcomes of CEE/MPA Versus CEE
Condition
CEE/MPA (Prempro)
CEE (Premarin)
CHD5,6
↑
NS
5,6
Stroke
↑
↑
Breast cancer5,6
↑
NS
↑
NS
5,6
VTE
Colorectal cancer5,6
↓
NS
5,6
Hip fracture
↓
↓
Dementia8,11,a
↑
NS
↑, statistically significant increased risk; ↓, statistically significant decreased risk; NS, not
significant.
CEE, conjugated equine estrogen; MPA, medroxyprogesterone acetate; CHD, coronary heart
disease; VTE, venous thromboembolism.
a
Women’s Health Initiative Memory Study involving subset of Women’s Health Initiative,
participants 65 and older.
210 DRUG BENEFIT TRENDS June 2008
or equivalent) formulations of HT
effectively reduce menopausal vasomotor symptoms,31-34 although
some women may need a standard
(0.625 mg CEE or equivalent) or
higher dose (1.25 mg CEE) of HT to
achieve an optimum response. Two
trials that directly compared lowdose (0.3 CEE) with standard-dose
(0.625 CEE) HT found no differences
in the relief of vasomotor symptoms.34,35 In addition, studies have
demonstrated that low-dose HT has
short-term beneficial effects on bone
mineral density36 and lipids and lipoproteins in menopausal women37;
minimal impact on coagulation factors37-39; and reduced likelihood of
causing adverse effects, such as irregular or heavy bleeding and breast
tenderness.34,40
Although evidence regarding
the long-term safety of low-dose HT
is still lacking, available data suggest
that low-dose HT may attenuate
some of the risks associated with
standard-dose HT. In the Nurses’
Health Study, an 8-year observational study of nearly 49,000 postmenopausal women, those receiving
standard dose CEE had a 35% increased risk of stroke (relative risk
[RR], 1.35; 95% CI, 1.08 to 1.68) and a
26% increased risk of breast cancer
(RR, 1.26; 95% CI, 0.96 to 1.65) compared with a 6% reduced risk of
stroke (RR, 0.54; 95% CI, 0.28 to 1.06)
and a 23% reduced risk of breast cancer (RR, 0.87; 95% CI, 0.44 to 1.73), respectively, among women who were
receiving low-dose CEE.41,42 Observational studies have revealed a
dose-response relationship between
HT and VTE risk. In 1 study, lowdose HT (0.325 mg/d CEE) was associated with a 2-fold increased risk
of VTE (RR, 2.1; 95% CI, 0.4 to 11.1)
compared with a 7-fold increased
risk with standard-dose HT (0.625
mg/d CEE [RR, 6.9; 95% CI, 1.5 to
33.0]).43 Similarly, another study reported a 4-fold increased risk of VTE
0806DBT203501hanlay 6/5/08 4:13 PM Page 211
Table 2. Absorption of Transdermal HT Products Indicated for the Relief of Moderate to
Severe Vasomotor Symptoms in Postmenopausal Women65
Available Dose(s)
of Estradiol (mg)
Estradiol
Delivery Rate
at the Lowest
Available Dosage
(mg/d)a
Divigel 0.1% (17-estradiol)
0.25, 0.5, 1.0
0.003
Elestrin 0.06% (17-estradiol)
0.52, 1.04
EstroGel 0.06% (17-estradiol)
Cmin
(pg/mL)
Cmax
(pg/mL)
9.8
N/A
14.7
0.0125
15.4
9.4
21.6
0.75
0.035
28.3
N/A
46.4
2.87, 4.8, 8.625
0.05
63
N/A
70.2
1.53
0.021
19.6
11.3
36.4
Alora (17-estradiol)
0.75, 1.5, 2.3, 3.0
0.025
18.6
N/A
N/A
Climara (17-estradiol)
2, 2.85, 3.8, 4.55
0.025
22
17
32
Esclim (17-estradiol)
5, 7.5, 10
0.025
17.8
15.5
24.5
Estraderm (17-estradiol)
4, 8
0.05
32
N/A
N/A
Vivelle-Dot (17-estradiol)
0.39, 0.585, 0.78, 1.17 0.025
34
30
46
Product
Cavg
(pg/mL)
Estradiol gels
Estradiol lotions
Estrasorb (17-estradiol)
Estradiol spray mist
Evamist (17-estradiol)
Estradiol transdermal patches
Cavg, mean serum concentration; Cmin, trough serum concentration; Cmax, peak serum concentration.
a
Estradiol delivery rates are associated with serum concentrations shown in adjacent columns.
(RR, 3.7; 95% CI, 1.3 to 10.2) among
patients receiving doses of less than
or equal to 0.625 mg/d CEE compared with a 7-fold increased risk
among those receiving doses of more
than 0.625 mg/d CEE.44
• Results were based on a specific
mode of drug delivery and may not
apply to other delivery modes. At
the time the WHI studies were conducted, oral CEE was the most common form of HT used in the United
States. Today, several different methods of transdermal HT (patch, gel,
spray) are available. Emerging evidence indicates that transdermal estrogen delivery may have some significant advantages compared with
conventional oral estrogen formulations, including more stable blood
levels of estrogens, lower exposure
to exogenous estrogens, lower risk
of VTE, and hormonal physiological states similar to perimenopause
(Table 2). Whereas oral estrogens are
subject to first-pass metabolism by
the liver and gut wall, transdermal
estrogen delivery avoids first-pass
hepatic metabolism45,46; this difference in metabolism has several important consequences. First, initial
metabolism by the liver and gut
results in fluctuating blood levels
of orally administered estrogens,
whereas transdermal administration
produces more stable serum concentrations of estrogens.47 Second,
first-pass metabolism necessitates
the administration of high doses of
exogenous estrogens to compensate
for the loss of as much as 30% of a
dose of oral estrogen, which is inactivated before reaching systemic
circulation.46
In contrast, transdermal systems
deliver the lowest effective dose of
estradiol,46 which is consistent with
current recommendations for HT,14,15
and may reduce the risk of adverse
effects.47 First-pass hepatic metabolism alters hepatic protein synthesis
and increases levels of triglycerides,
C-reactive protein, and sex hormone–binding globulin, while transdermal delivery of estrogens is not
associated with these effects.47 CliniJune 2008 DRUG BENEFIT TRENDS 211
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Table 3. Comparison of Transdermal Hormone Therapies
Advantages
Estradiol
Spray
Invisible following application
√
Dries quickly
√
N/A
Covers a small area of skin
√
√
No-touch application
√
√
Adhesive Patches
√
Risk of partner transfer
No site irritation; no removal residue
√
√
Less frequent dosing
Dosing can be adjusted without a
new prescription
cal trials have documented that oral
estrogens increase risk factors for
VTE, such as markers of inflammation, coagulation activation, and
fibrinolysis,48-51 while transdermal
estrogens have no appreciable hemostatic effects.50 The recently published final analysis of the Estrogen and Thromboembolism Risk
(ESTHER) case-control study found
a 4-fold greater risk of VTE among
postmenopausal women who received oral estrogen compared with
women who did not use HT.52 The
same study found that transdermal
HT was not associated with an increased risk for VTE (odds ratio
[OR], 0.9; 95% CI, 0.4 to 2.1).52
In addition to differences related to
first-pass metabolism, oral CEE results in a ratio of estrone to estradiol
of 5:1 to 7:1,53 which is more reflective of the postmenopausal state,46
while transdermal HT produces an
estradiol-estrone ratio of about 1:1,
which more closely resembles the
perimenopausal state.46
HT Transdermal Delivery Modes
Currently available FDA-approved
transdermal HT formulations include patches (eg, Alora, Climara,
212 DRUG BENEFIT TRENDS June 2008
Gels and Lotion
√
√ (weekly)
√
Estraderm, Vivelle, Vivelle-Dot), gels
(eg, Divigel, Elestrin, EstroGel), lotions (eg, Estrasorb) and the newest
formulation, estradiol spray (Evamist). These transdermal HT formulations are associated with low plasma drug concentrations, as can be
seen in Table 2. All transdermal formulations are expected to provide
similar benefits compared with conventional oral HT, but differ with
respect to convenience, tolerability,
and dosing (Table 3). Estradiol spray,
gels, and lotions are invisible once
applied, whereas transdermal patches are visible (unless hidden by
clothing). Transdermal patches and
estradiol spray may be applied more
quickly because of a faster drying
rate for spray (2 minutes54) compared with gels and lotions (up to
5 minutes55) and less skin area to
cover for spray54 and patches56 compared with gels and lotions.55,57-59
Both estradiol spray and transdermal patches offer the convenience
of “no-touch” application and ensure minimal risk of transfer, while
gels and lotions require hand washing following application and may
transfer to others through skin-toskin contact.54,55,57-59 Whereas up to
√
57% of patients using transdermal
patches experience application site
reactions,60 the most commonly reported reason for discontinuation of
transdermal estradiol,61 such reactions are much less common with
estradiol spray (1.3%)54 and gels or
lotions (less than 1% to 12.5%).55,57-59
Transdermal patches offer less frequent (weekly) dosing56 compared
with once-daily administered spray
and gels or lotions.54,55,59,62 However,
estradiol spray and gels or lotions
have greater dosing flexibility because the dosage may be increased
or decreased by changing the number of sprays54 or amount of gel or lotion administered,55,59,62 while transdermal patches require a new prescription to adjust the dose.56
Conclusion
Women with moderate to severe vasomotor symptoms and their physicians must weigh the risks of HT
against the benefits of symptom relief
and minimize risks by using the lowest effective doses for the shortest
possible duration.14,15 The WHI studies, designed to examine the riskbenefit profile associated with HT
use, have generated considerable
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Menopause
confusion as well as controversy,
and their results may not apply to
younger, symptomatic menopausal
women and those who use alternative HT regimens (low-dose, transdermal delivery).63 Emerging data
suggest that lower doses and transdermal delivery of hormones may
be safer than the standard-dose oral
conventional HT regimen used in the
WHI studies,63,64 although long-term
studies are needed to confirm these
benefits. Today, women and their
physicians may choose among several FDA-approved transdermal products, including estradiol patches, gels
and lotions, and a spray mist.65
■
Acknowledgments
Funding for this research was provided
by Ther-Rx Corp, Bridgeton, Mo.
We also thank Amy Bronstone, PhD, for
her assistance in writing this article and
Mary Bordeaux for her contribution to
the content of this work.
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